Hsp90 is an essential molecular chaperone with a highly specialized function (1-3). Under physiological conditions, it regulates the folding, transport, maturation, and degradation of a diverse, but select set of client proteins, many of which are key regulators of cell signalling circuitry (4). Hsp90's clients include transcription factors and kinases that regulate processes as diverse as cell growth and division, development, apoptosis, immunity, and responses to hormones and other environmental signals (5). Details vary, but a common feature of many Hsp90 clients is a tendency to dwell in metastable, incompletely folded states. These proteins dynamically cycle through Hsp90 complexes until folding and activation are engendered by the binding of a ligand, insertion into a membrane, post-translational modification, or assembly with partner proteins.
An emergent property of Hsp90's function in chaperoning regulators of cell circuitry is a capacity to buffer the expression of genetic and epigenetic variation and release it in response to environmental stress (6-8). Under normal growth conditions, Hsp90 is expressed at much higher levels than are required for basal function. It is thereby intrinsically positioned to buffer variation. Protein folding, however, is exquisitely sensitive to diverse forms of environmental stress. Under such conditions, Hsp90 is induced, together with other heat shock proteins, to cope with this problem. Depending upon the genetic variation that has accumulated in particular genomes, however, the cellular demand for Hsp90 can exceed its level of induction. In the fly Drosophila melanogaster, the plant Arabidopsis thaliana, and likely in many other organisms, compromising Hsp90's buffering capacity by environmental stress, drugs, or mutations produces an extraordinary array of new phenotypes. While some of these phenotypes may be stochastic, others depend upon previously silent variation that can act in a combinatorial manner to produce new traits (6, 7). Importantly, after several generations of selection, polymorphisms that had been cryptic in progenitor organisms can be enriched in their progeny to the point that the phenotypes they produce are stably expressed even in one absence of stress (6). Thus, Hsp90 may play an important role in evolution by serving as a capacitor for the storage and release of genetic variation.